This proposal focuses on the application of therapeutic ultrasound in improving ocular drug delivery. The proposed research will address an important clinical problem since it is often difficult to achieve therapeutic levels of drugs at the treatment sites inside the eye. Cornea, which is a dominant route for delivery of ophthalmic drugs, acts as a biological barrier and usually less than 10% of the applied drug can penetrate into the front of the eye with virtually no penetration into the back of the eye. We have previously shown that exposing rabbit cornea to therapeutic ultrasound can lead to up to 10 times more delivery of a drug-mimicking compound into the eye, with only minimal changes in the corneal tissues. We are now proposing to work on clinically relevant problems that can be addressed with ultrasound-enhanced drug delivery, such as promoting delivery of antibiotics and anti-inflammatory drugs for treatment of eye infections and inflammations. Our main objective is to find ultrasound parameters that can provide clinically relevant enhancement of the delivery of medications into the eye, while producing only minor and reversible changes in the eye tissues. First, we are proposing to work on the development of a theoretical simulation model which can predict the permeability of the cornea for ocular medications (of different hydrophilicity and molecular size), before and after application of ultrasound at various parameters (frequency, intensity, duration, and duty cycle). We will then develop therapeutic ultrasound devices for drug delivery that will allow complete control of different ultrasound parameters. These devices will be tested in in-vitro and in-vivo experiments. The experiments will utilize eyes of albino rabbits, which are a usual animal model for ocular drug delivery. Feasibility of ultrasound application in ocular drug delivery will be determined by using standard methods for measurement of the amounts of drug that crosses the cornea which is exposed to ultrasound or sham-treated (no ultrasound application). Safety of the treatment will be determined by using ophthalmic and histological observations of ultrasound-induced changes in the corneal structure and barrier properties, immediately after the treatment and up to 14 days after the treatment. Our long-term goal is to develop an inexpensive, fast and minimally-invasive ultrasound method for drug delivery that can be applied in an outpatient clinic or in the hospital to allow medications to penetrate into eye tissues with infection/inflammation and deliver the drugs at a sufficient concentration to fight bacteria, fungi or viruses before they produce a permanent loss in vision. Public Health Relevance: Major eye infections/inflammations often result in the loss of vision due to corneal scarring. We believe that therapeutic ultrasound can offer an inexpensive and relatively simple method for improved delivery of medications into the eye. This method may allow faster treatment of corneal infections/inflammations as compared to currently used methods, thus potentially preventing permanent damage of the eye tissues.